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Kidney fibrosis and renal tubular epithelial-to-mesenchymal transition (EMT) are the main pathological changes of diabetic nephropathy (DN), which eventually leads to end-stage renal disease. Previous studies have suggested that echinacoside (ECH) is antifibrotic in the liver. However, the effect of ECH on kidney fibrosis in DN and its mechanisms are unknown. This study was performed to explore the effect of ECH on kidney fibrosis and also the molecular mechanisms of ECH in a db/db mice model of DN. Our results showed that, relative to db/db mice, the mice in the ECH group had an improved general state and reduced blood glucose and 24-hour urinary protein levels. The deterioration of renal function was delayed due to treatment with ECH. We also observed that ECH can improve histopathological findings in the kidneys of db/db mice, including collagen deposition, mesangial cell and mesangial matrix hyperplasia, basement membrane thickening, and podocyte reduction. Moreover, ECH inhibited the TGF-β1/Smads signaling pathway, downregulated fibronectin (FN), collagen IV, and alpha-smooth muscle actin (α-SMA) levels, and upregulated E-cadherin level in the db/db mice model of DN. Our findings indicate that ECH has a therapeutic effect on DN, including the inhibition of renal tubular EMT and kidney fibrosis. Furthermore, ECH inhibits kidney fibrosis through regulation of the TGF-β1/Smads signaling pathway.

Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.

Intestinal fibrosis is induced by excessive myofibroblast proliferation and collagen deposition, which has been regarded as a general pathological feature in inflammatory bowel disease (IBD). Therefore, identifying clinical markers and targets to treat and prevent intestinal fibrosis is urgently needed. The traditional Chinese medicine maggot, commonly known as “wu gu chong”, has been shown to reduce oxidative stress and alleviate inflammation in chronic colitis. This study investigated the mechanisms underlying the effects of maggot extract (ME) on inflammation-associated intestinal fibrosis in TGF-β1-stimulated human intestinal fibroblasts (CCD-18Co cells) and dextran sodium sulphate (DSS)-induced chronic colitis murine model. To assess the severity of inflammation and fibrosis, histological and macroscopic evaluation were carried out. The results showed that ME was a significant inhibitor of body weight loss and colon length shortening in mice with chronic colitis. In addition, ME suppressed the intestinal fibrosis by downregulating TGF-β1/SMADs pathway via upregulation of Nrf2 expression at both protein and mRNA levels. ME markedly increased the expression of Nrf2, thus resulting in a higher level of HO-1. After treatment with Nrf2 inhibitor (ML385) or siRNA-Nrf2 for deactivating Nrf2 pathway, the protective effects of ME were abolished both in vitro and in vivo . Moreover, the histopathological results for the major organs of DSS mice treated with ME showed no signs of clinically important abnormalities. Treatment with ME had no effect on the viability of CCD-18Co cells, suggesting its low in vitro cytotoxicity. Furthermore, ME could mediate intestine health by keeping the balance of the gut microbes through the enhancement of beneficial microbes and suppression of pathogenic microbes. In conclusion, this is the first ever report demonstrating that ME ameliorates inflammation-associated intestinal fibrosis by suppressing TGF-β1/SMAD pathway via upregulation of Nrf2 expression. Our findings highlight the potential of Nrf2 as an effective therapeutic target for alleviating intestinal fibrosis.

Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, Gentianella amarella subsp. acuta (Michx.) J.M.Gillett ( G. acuta ) is a kind of tea used to prevent cardiovascular diseases. Bellidifolin (BEL) is an active xanthone molecule from G. acuta that protects against myocardial damage. However, the effects and mechanisms of BEL on myocardial fibrosis have not been reported. In vivo , BEL dampened isoprenaline (ISO)-induced cardiac structure disturbance and collagen deposition. In vitro, BEL inhibited transforming growth factor (TGF)-β1-induced cardiac fibroblast (CF) proliferation. In vivo and in vitro , BEL decreased the expression of α-smooth muscle actin (α-SMA), collagen Ⅰ and Ⅲ, and inhibited TGF-β1/Smads signaling. Additionally, BEL impeded p38 activation and NR4A1 (an endogenous inhibitor for pro-fibrogenic activities of TGF-β1) phosphorylation and inactivation in vitro . In CFs, inhibition of p38 by SB203580 inhibited the phosphorylation of NR4A1 and did not limit Smad3 phosphorylation, and blocking TGF-β signaling by LY2157299 and SB203580 could decrease the expression of α-SMA, collagen I and III. Overall, both cell and animal studies provide a potential role for BEL against myocardial fibrosis by inhibiting the proliferation and phenotypic transformation of CFs. These inhibitory effects might be related to regulating TGF-β1/Smads pathway and p38 signaling and preventing NR4A1 cytoplasmic localization.

Zhipin Zhou, Department of Pharmacy, Liuzhou People’s Hospital, Liuzhou, 545006, People’s Republic of China, Email gxzhouzhipin@126.comAbstract: Liver disease is a common chronic illness with increasing incidence and mortality. Exosomes are small membrane vesicles (30– 200 nm) containing complex RNAs and proteins that serve as mediators of intercellular communication. The role of exosomes in liver disease is complex and sometimes contradictory. In certain situations, they may suppress liver disease, whereas in others, they promote its progression. This duality raises important questions regarding the overall impact of these drugs on the treatment of liver disease. The Transforming Growth Factor-beta1 (TGF-β 1)/Smads signaling pathway plays a significant role in the occurrence and development of liver diseases, and exosomes mediate liver disease by regulating the TGF-β 1/Smads signaling pathway. Research has shown that Traditional Chinese Medicine (TCM) can exert liver-protective effects by influencing exosomes to modulate the TGF-β 1/Smads signaling pathway. Using keywords such as “exosomes”, “TGF-β 1/Smads signaling pathway”, “liver fibrosis”, “hepatocellular carcinoma”, “liver diseases”, and “traditional Chinese medicine”, this article reviews the literature from databases, including CNKI, PubMed, and SCOPUS. It summarizes how exosome-mediated regulation of the TGF-β 1/Smads signaling pathway affects the development of liver diseases and compiles relevant studies on the anti-liver disease effects of TCM through exosomal modulation of this pathway.

Guidong Huang,1 Zhipin Zhou2 1Department of Pharmacy, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, People’s Republic of China; 2Department of Pharmacy, Liuzhou People’s Hospital, Liuzhou, People’s Republic of ChinaCorrespondence: Zhipin Zhou, Department of Pharmacy, Liuzhou People’s Hospital, Liuzhou, 545006, People’s Republic of China, Email gxzhouzhipin@126.comAbstract: Liver disease is a common chronic illness with increasing incidence and mortality. Exosomes are small membrane vesicles (30– 200 nm) containing complex RNAs and proteins that serve as mediators of intercellular communication. The role of exosomes in liver disease is complex and sometimes contradictory. In certain situations, they may suppress liver disease, whereas in others, they promote its progression. This duality raises important questions regarding the overall impact of these drugs on the treatment of liver disease. The Transforming Growth Factor-beta1 (TGF-β 1)/Smads signaling pathway plays a significant role in the occurrence and development of liver diseases, and exosomes mediate liver disease by regulating the TGF-β 1/Smads signaling pathway. Research has shown that Traditional Chinese Medicine (TCM) can exert liver-protective effects by influencing exosomes to modulate the TGF-β 1/Smads signaling pathway. Using keywords such as “exosomes”, “TGF-β 1/Smads signaling pathway”, “liver fibrosis”, “hepatocellular carcinoma”, “liver diseases”, and “traditional Chinese medicine”, this article reviews the literature from databases, including CNKI, PubMed, and SCOPUS. It summarizes how exosome-mediated regulation of the TGF-β 1/Smads signaling pathway affects the development of liver diseases and compiles relevant studies on the anti-liver disease effects of TCM through exosomal modulation of this pathway.Keywords: exosome, TGF-β 1/Smads signaling pathway, liver disease, traditional Chinese medicine

Background Resveratrol extracted from grape has been an ideal alternative drug in the therapy of different cancers including colorectal cancer (CRC). Since the underlying mechanisms of resveratrol on the invasion and metastasis of CRC have not been fully elucidated, and epithelial-to-mesenchymal transition (EMT) is a key process associated with the progression of CRC, here we aimed to investigate the potential mechanism of resveratrol on the inhibition of TGF-β1-induced EMT in CRC LoVo cells. Methods We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo. In vivo , the impact of resveratrol on invasion and metastasis was investigated by mice tail vein injection model and mice orthotopic transplantation tumor model. In vivo imaging was applied to observe the lungs metastases, and hemaoxylin-eosin (HE) staining was used to evaluate metastatic lesions. In vitro , impact of resveratrol on the migration and invasion of LoVo cells was evaluated by transwell assay. Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation. Epithelial phenotype marker E-cadherin and mesenchymal phenotype marker Vimentin were detected by western blot and immunofluorescence. Promoter activity of E-cadherin was measured using a dual-luciferase assay kit. mRNA expression of Snail and E-cadherin was measured by RT-PCR. Results We demonstrated that, resveratrol inhibited the lung metastases of LoVo cells in vivo . In addition, resveratrol reduced the rate of lung metastases and hepatic metastases in mice orthotopic transplantation. In vitro, TGF-β1-induced EMT promoted the invasion and metastasis of CRC, reduced the E-cadherin expression and elevated the Vimentin expression, and activated the TGF-β1/Smads signaling pathway. But resveratrol could inhibit the invasive and migratory ability of LoVo cells in a concentration-dependent manner, increase the expression of E-cadherin, repress the expression of Vimentin, as well as the inhibition of TGF-β1/Smads signaling pathway. Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT. Conclusions Our new findings provided evidence that, resveratrol could inhibit EMT in CRC through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in CRC.

Podocyte dedifferentiation and mesangial cell (MC) activation play an important role in many glomerular diseases associated with fibrosis. MicroRNA-21 (miR-21) is closely linked to renal fibrosis, but it is unknown whether and how miR-21 promotes podocyte dedifferentiation and MC activation and whether astragaloside IV (AS-IV) improves renal function and fibrosis through the regulation of miR-21. Cultured MCs, primary mouse podocytes, and diabetic KK-Ay mice were treated with AS-IV. Cell transfection, Western blot, real-time PCR, immunofluorescence assay, immunohistochemical assay, and electronic microscopy were used to detect the markers of podocyte dedifferentiation and MC activation and to observe the renal morphology. Our data showed that miR-21 expression was increased and that AS-IV decreased miR-21 levels in cells, serum, and kidney. Overexpressed miR-21 promoted podocyte dedifferentiation and MC activation, and treatment with AS-IV reversed this effect. Furthermore, the overexpression of miR-21 activated the β-catenin pathway and the transforming growth factor (TGF)-β1/Smads pathway in the process of podocyte dedifferentiation and MC activation, which was abolished by AS-IV treatment. In addition, both the Wnt/β-catenin pathway inhibitor XAV-939 and the TGF-β1/Smads pathway inhibitor SB431542 reversed the effect of AS-IV. Furthermore, AS-IV improved renal function and fibrosis in diabetic KK-Ay mice. Our results indicated that AS-IV ameliorates renal function and renal fibrosis by inhibiting miR-21 overexpression-induced podocyte dedifferentiation and MC activation in diabetic kidney disease. These findings pave way for future studies investigating AS-IV as a potential therapeutic agent in the management of glomerular diseases.

Salvianolic acid A (SAA) is one of the major components in Salvia miltiorrhiza Bge., with various pharmacological activities, and is likely to be a promising agent for the treatment of kidney diseases. The purpose of this study was to explore the protective effect and mechanisms of SAA on kidney disease. In this study, the improvement effects of SAA (10, 20, 40 mg/kg, i.g.) on kidney injury rats were investigated by detecting the levels of KIM-1, NGAL in serum and UP in the urine of AKI model rats established with gentamicin, as well as the levels of SCr and UREA in serum and IL-6, IL-12, MDA and T-SOD in the kidneys of CKD model rats established with 5/6 nephrectomy. HE and Masson staining were used to observe the histopathological changes in the kidney. Network pharmacology and Western blotting were used to explore the mechanism of SAA in improving kidney injury. The results showed that SAA improved kidney function in kidney injury rats by reducing the kidney index and pathological injury by HE and Masson staining, reducing the levels of KIM-1, NGAL and UP in AKI rats and UREA, SCr and UP in CKD rats, as well as exerting anti-inflammatory and anti-oxidative stress effects by inhibiting the release of IL-6 and IL-12, reducing MDA and increasing T-SOD. Western blotting results showed that SAA significantly reduced the phosphorylation levels of ERK1/2, p38, JNK and smad2/3, and the expression of TLR-4 and smad7. In conclusion, SAA plays a significant role in improving kidney injury in rats and the mechanism may be achieved by regulating the MAPKs and TGF-β1/smads signaling pathways.

[This corrects the article DOI: 10.3389/fphar.2021.655531.].[This corrects the article DOI: 10.3389/fphar.2021.655531.].